1. Field of the Invention
The invention relates to polycyclic nucleotide xanthine phosphodiesterase V inhibitors.
2. Description of Related Art
Phosphodiesterase (“PDE”) V inhibitor compounds are described by Kenneth J. Murray in Phosphodiesterase VA Inhibitors, DN & P 6(3), pp. 150-156 (April, 1993), which is hereby incorporated herein by reference in its entirety, to have potential therapeutic value for a number of physiological disorders. One compound disclosed in the Murray article is MIMAX, a polycyclic xanthine PDE V inhibitor substituted at its 8-position with a —NHCH3 group.
U.S. Pat. No. 5,409,934, which is hereby incorporated herein by reference in its entirety, discloses a series of xanthine PDE V inhibitors that are substituted at the 8-position with, among other possibilities, one of the following groups: —NO2, —NRsRt or —NR6SO2R5, where Rs and Rt, independently of one another, are each a hydrogen atom or an alkyl group, or Rs and Rt, together with the nitrogen atom to which they are both attached, form a phthalimido group, R5 is an alkyl or aryl group, and R6 is a hydrogen atom or —SO2R7, where R7 is an alkyl or aryl group.
U.S. Pat. No. 5,470,579, which is hereby incorporated herein by reference in its entirety, discloses a xanthine PDE V inhibitor having a substituted or unsubstituted —NH2 group at the 8-position, for example, —NHR, where R is a C1-C6 alkyl group.
WO 93/23401, which is hereby incorporated herein by reference in its entirety, discloses xanthine PDE V inhibitors that are substituted at the 8-position with —NH(CH2)2CH(CH2OR4)2.
WO 92/05176, which is hereby incorporated herein by reference in its entirety, discloses 8-acylaminoxanthine PDE V inhibitors that are substituted at the 8-position with —NHCOC6H5COOH.
WO 92/05175, which is hereby incorporated herein by reference in its entirety, discloses 8-aminoxanthine PDE V inhibitors that are substituted at the 8-position with —NH2 or —NHR, where R is an alkyl, arylalkyl or unsaturated heterocyclic (e.g., heteroaryl) group.
Specific PDE V inhibitors have been found useful for specific indications. For example, the use of PDE V inhibitors for treating impotence has met with commercial success with the introduction of sildenafil citrate, better known as Viagra® (Pfizer, NY, N.Y.) The chemistry and use of Viagra®, including its mechanism of action in treating erectile dysfunction, are taught in EP 0 702 555 B1, which is hereby incorporated herein by reference in its entirety. Additional PDE V inhibitors useful for treating erectile dysfunction are disclosed in WO 99/24433, which is hereby incorporated herein by reference in its entirety.
Erectile dysfunction is a treatable and highly recognized health concern, affecting more than 30 million men in the United States, including one in four over age 65. Erectile dysfunction occurs when a man consistently is unable to sustain an erection sufficient for conducting sexual intercourse, In the past, psychological reasons were the most common explanation for erectile dysfunction or it was considered a natural part of aging. However, researchers today acknowledge that more than 70 percent of instances of erectile dysfunction are due to physical or medical problems. There are several factors that may contribute to erectile dysfunction, including,                Poor blood circulation—atherosclerosis or hardening of the arteries, high blood pressure and high cholesterol.        Neurological disorders—multiple sclerosis, Alzheimeres disease and Parkinson's disease.        Hormone imbalances—diabetes, thyroid disorders and low testosterone levels.        Trauma—spinal cord injury, prostate surgery or other trauma to the pelvic area.        Prescription and over-the-counter medications—blood pressure medications, antidepressants and certain drug combinations.        Lifestyle habits—smoking, alcohol abuse and using illegal drugs.        
U.S. Pat. No. 5,939,419 and U.S. Pat. No. 5,393,755, both of which are hereby incorporated herein by reference in their entirety, disclose polycyclic guanine PDE V derivatives that are useful for the treatment of cardiovascular and pulmonary disorders.
As has been shown by the representative art cited above, certain xanthine/guanine PDE V inhibitors have been found to be useful for treating cardiovascular and pulmonary disorders, while some others have been found useful for treating impotence. It has been further shown that certain xanthine PDE V inhibitors can be substituted at the 8-position by a variety of groups, including nitro and unsubstituted or substituted amino groups. The substituted amino groups include saturated heterocycles, where the nitrogen atom and its substituents together form an unsaturated heterocyclic group (e.g., —NRxRy can form a heterocycle).
It is an object of this invention to provide a polycyclic xanthine PDE V inhibitor that possesses beneficial therapeutic properties.
It is a further object of the invention to provide a polycyclic xanthine PDE V inhibitor that has especially useful pharmacological properties.
It is yet another object of the invention to provide a polycyclic xanthine PDE V inhibitor that has good metabolic stability.
It is still another object of the invention to provide a polycyclic xanthine PDE V inhibitor that is effective for treating a variety of physiological symptoms and diseases in which PDE V plays a role.
It is also an object of the invention to provide a polycyclic xanthine PDE V inhibitor that is especially effective for treating erectile dysfunction with minimal side effects.
These and other objects of the invention will become apparent as the description progresses.